Bone metabolism is dependent on the overall activity of osteoblasts which control bone formation and osteoclasts which control bone resorption. Abnormality of bone metabolism is considered to be caused by an imbalance of the bone formation and the bone resorption. Osteoporosis, hypercalcemia, Paget's disease, renal osteodystrophy, chronic rheumarthritis, osteoarthristis, and the like are known as diseases accompanying abnormality of bone metabolism. Osteoporosis is a typical disease caused by such abnormality of bone metabolism. This disease is generated when bone resorption by osteoclasts exceeds bone formation by osteoblasts. The disease is characterized by a decrease in both the bone calcified material and the bone matrix. Although the mechanism of this disease is not completely elucidated, the disease causes aches in bones, makes them fragile, and may result in fracturing. This disease is becoming a social problem because it increases the number of bedridden aged persons as the aged population becomes larger. Development of therapeutic agent for this disease is urgently desired. Disease due to a decrease in bone mass is expected to be cured by suppressing bone resorption, accelerating bone formation, or improving the balance between bone resorption and formation. Bone formation is expected to increase by accelerating proliferation, differentiation, or activation of osteoblasts which form bone, or by suppressing proliferation, differentiation, or activation of osteoclasts which resorb bone. In recent years, strong interest has been directed to hormones, low molecular weight substances, or physiologically active proteins exhibiting such activities, and energetic basic research and development is underway on these subjects.
Drugs such as a calcitonin agents, active-form vitamin D3 agents, hormone agents containing estradiol, ipriflavon, vitamin K2, and bisphosphonate compounds have already been known as drugs to treat and shorten the treatment period of diseases related to bone. Clinical tests are in progress on active-form vitamin D3 derivatives, estradiol derivatives, and bisphosphonate compounds of the second and the third generation to develop therapeutic agents with excellent efficacy and minimal side effects.
However, therapies using these agents were found not necessarily satisfactory in terms of efficacy and therapeutic results. Development of novel therapeutic agents which are safer and with higher efficacy is urgently desired. Some agents used for the treatment of diseases related to bone metabolism are used only limitedly due to their side effects. Furthermore, treatments using two or more agents in combination are currently the mainstream in the treatment of diseases related to bone metabolism such as osteoporosis. From such a point of view, development of drugs having action mechanisms different from those of conventional drugs, and exhibiting a higher efficacy and minimal side effects is desired.
As mentioned above, the cells controlling bone metabolism are osteoblasts and osteoclasts. These cells are known to have close mutual interactions called “coupling”. Specifically, cytokines such as Interleukins 1(IL-1), 3(IL-3), 6(IL-6), and 11(IL-11), granulocytic macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), Interferon-γ (IFN-γ), tumor necrosis factor a (TNF-α), and transforming growth factor-β (TGF-β), secreted by osteoblastic stromal cells are known to accelerate or suppress differentiation or maturation of osteoclasts (Raisz: Disorders of Bone and Mineral Metabolism, 287-311, 1992; Suda et al.: Principles of Bone Biology, 87-102, 1996; Suda et al.: Endocrine Reviews, 4, 266-270, 1995, Lacey et al.: Endocrinology, 186, 2369-2376, 1995). It has been reported that osteoblastic stromal cells play an important role in the differentiation and maturation of osteoclasts, as well as in osteoclast functions such as bone resorption by mature osteoclasts, through cell-to-cell contact with immature osteoclast precursors or mature osteoclasts.
A factor called osteoclast differentiation factor (ODF, Suda et al.: Endocrine Rev. 13, 66-80, 1992; Suda et al.: Bone 17, 87S-91S, 1995) is thought to be expressed on the membrane of osteoblastic stromal cells and involved in the formation of osteoclasts through cell-to-cell contact. According to this hypothesis, an ODF receptor is present in the precursor cells of osteoclasts. However, so far neither the ODF nor the receptor has been purified or identified. There are also no reports relating to their characteristics, action mechanism, or structure. Thus, the mechanism involved in differentiation and maturation of osteoclasts has not yet been sufficiently elucidated. Clarification of this mechanism will greatly contribute not only to the basic medicine, but also to the development of novel drugs for the treatment of diseases associated with abnormality of bone metabolism.
The present inventors have conducted extensive studies in view of this situation and discovered an osteoclastogenesis inhibitory factor (OCIF) in a culture broth of human embryonic lung fibroblast, IMR-90 (ATCC Deposition No. CCL186) (WO 96/26217).
The present inventors have been successful in cloning DNA encoding OCIF, production of recombinant OCIF in animal cells, and confirmation of in vivo pharmaceutical effects (improving effect on bone metabolism, etc.) of the recombinant OCIF. OCIF is expected to be used as an agent for the prevention or treatment of diseases related to abnormality of bone metabolism, with higher efficacy than conventional drugs and less side effects.